Cryptococcosis is caused by the opportunistic pathogen, Cryptococcus neoformans (C. neoformans) and the primary pathogen, Cryptococcus gattii (C. gattii). The disease manifests as pneumonia and meningitis. The most common risk for cryptococcosis caused by C. neoformans is AIDS, in contrast to C. gattii, which is more commonly reported to infect apparently normal individuals. Importantly, the components contributing to their susceptibility to infection with C. gattii remain largely unknown. Recently, colleagues at the National Institutes of Health (NIH) reported that the presence of anti- granulocyte-macrophage colony-stimulating factor (?GM-CSF) neutralizing autoantibodies may contribute to infection of immunocompetent individuals with C. gattii. As this was the first study describing any factor influencing one's vulnerability to this primary pathogen, not all of the patients infected with C. gattii had ?GM- CSF autoantibody. Thus, there could be other contributing factors, such as a genetic mutation, to explain susceptibility within this population f non-HIV individuals. This project is composed of two interconnected aims of the role of monocytes in host susceptibility to C. gattii infection. The long-term goal of this project is to uncover the underlying determinants of host susceptibility to C. gattii. To achieve this goal, the aims of this application are: 1) to determine how a dysfunction in autophagy alters host resistance to C. gattii using mouse and cell culture model systems and 2) to employ a discovery study to analyze monocytes from previously healthy, non-HIV patients infected with C. gattii to identify genetic predispositions to the disease.